ABSTRACT Alzheimer?s disease (AD) is the most common and severe age-associated neurodegenerative dementia for which finding a resolving cure is a pressing national priority. The discovery of resilient individuals who remain cognitively intact despite the presence of AD neuropathology normally associated with a fully symptomatic stages of the disease, suggests that there is a way for the brain to evade dementia even in the face of AD. It follows that understanding the mechanism(s) involved in such extraordinary resistance would reveal targets for the development of a novel, effective therapeutic concept based on inducing cognitive resilience in anyone challenged with AD neuropathology. With this goal in mind, we have discovered that brain synapses in these unaffected individuals are resistant to the disrupting binding of toxic oligomers of both amyloid beta (A?) and tau (an event linked to onset of dementia in AD) and that this resistance is associated with the presence of higher numbers of neural stem cells (NSC) in the hippocampus as compared to either AD patients and control subjects. While these observations suggest a link between sustained neurogenesis and synaptic resistance to damaging amyloid oligomers, the involved mechanism (an obvious treatment target) remains unknown. Based on exciting new, compelling preliminary data involving exosomes specifically released from NSC as mediators of this phenomenon, in this project we will test the hypothesis that NSC-derived exosomes render synapses resistant to the disrupting binding of A? and tau oligomers and thus protect from memory deficits. Employing both ex vivo and in vivo models of A? and tau oligomer-induced synaptic dysfunction and cognitive impairment, in Specific Aim 1 we will test the hypothesis that NSC-derived exosomes reduce synaptic susceptibility to amyloid oligomers binding and its functional consequences. In Specific Aim 2 we will characterize microRNAs present in NSC-exosomes responsible for these effects. At the completion of the proposed studies we will have documented a previously unappreciated phenomenon of synaptic resistance to A? and tau oligomers mediated by NSC-exosomes and discovered specific miRNAs that can promote it. Given the translational value of miRNAs for drug development, this discovery will have a substantial impact in the field by illustrating targets for the development of an innovative treatment concept for AD centered on promoting synaptic resistance to toxic oligomers, a strategy expected to be effective in humans as suggested by the existence of NDAN subjects. A uniquely qualified investigative team has been assembled to successfully accomplish this project, bringing together expertise in AD molecular neurobiology (Taglialatela), NSC biology (Micci), biochemistry of amyloid proteins (Kayed), miRNA sequencing and analysis (Widen), electrophysiology and animal behavior (Krishnan).